Project Summary Skeletal bone mass and load-bearing capacity diminish as a result of hormonal and metabolic changes with aging, resulting in fractures at corticocancellous sites. Intermittent parathyroid hormone (iPTH) is the only FDA-approved anabolic treatment that improves bone mass and architecture. Mechanical loading synergistically amplifies the beneficial effects of PTH but the mechanism is not understood. Our preliminary data show that PTH is more effective at loaded sites that experience tension than those that are loaded in compression. In this exploratory proposal we aim to understand the interaction of mechanical loading and PTH treatment during osteoporosis, with the goal of enhancing the anabolic effects of PTH seen experimentally and clinically. Using a model of postmenopausal osteoporosis we will determine the role of loading mode in the response to intermittent PTH (iPTH) treatment in cortical bone and the contribution of activation of bone formation by PTH to the synergistic effect of iPTH and mechanical loading in cancellous bone. In Specific Aim 1 we will determine the differential effects of tensile and compressive loading on the synergistic anabolic response to iPTH and mechanical loading in a preclinical model of postmenopausal osteoporosis. In Specific Aim 2 we will establish if iPTH pre-treatment enhances the synergistic anabolic effects of iPTH and in vivo mechanical loading in cancellous bone of healthy and osteopenic mice. Both aims will use a female mouse model of postmenopausal osteoporosis combined with iPTH treatment and controlled tibial loading. Outcomes will include tissue architecture, bone cell activity, and protein localization by microCT, histomorphometry and immunohistochemistry. Mechanical behavior will also be assessed in Aim 2. These experiments will further our mechanistic understanding of the relationship between PTH and in vivo skeletal mechanical loading based on our novel hypothesis regarding the mechanisms of PTH action in postmenopausal osteoporosis. These experiments are critical to understanding the mechanisms underlying cancellous bone adaptation to loading and to developing strategies to inhibit age-related and postmenopausal bone loss and the resulting fractures. Our goal is to inform and direct future clinical treatment regimens and enable the effectiveness of PTH to be maximized clinically.